Biology subjects

Dourlen, P.

Publications and source records attributed to Dourlen, P..

4 recordsLinked to original sources

bioRxiv2025

BIN1 expression in the presynaptic compartment leads to isoform-specific synaptotoxicity

Alzheimers disease (AD) is characterized by a strong genetic predisposition and by an early loss of synaptic connectivity that strongly correlates with cognitive deficit. Some genetic determinants could contribute to synapse frailty toward AD pathology. However, the role of genetic determinants in AD pathogenesis remains poorly understood at the synaptic level. Here, we show that the expression of an isoform of the major AD susceptibility gene BIN1 in the presynaptic compartment results in synaptic loss. Using electrophysiology, we observed an early loss of synaptic transmission upon BIN1 isoform 1 (BIN1iso1) expression in Drosophila retinal photoreceptor neurons. This was not observed for the other human BIN1 isoforms tested, isoform 8 and isoform 9. Structural analysis of photoreceptor neuron synapses shows a strong accumulation of abnormally large vesicles in the presynaptic compartment, reminiscent of this same isoform-induced endosome defects in cell bodies. In addition, the expression of BIN1iso1 in motoneurons of the Drosophila neuromuscular junction alters the morphology of synaptic boutons, with a greater number and a smaller size of synaptic boutons, and the appearance of satellite boutons. As opposed to endosomal defects in cell body, modulating the Rab11 recycling endosome regulator did not prevent BIN1iso1 synaptotoxicity. To test if synaptic deficits are conserved in a mammalian model and to assert a presynaptic vs postsynaptic role for BIN1, we used rat primary neurons cultured in microfluidic devices that restrict gene expression modulation in particular neuron populations. We found a loss of synaptic connectivity only when expressing BIN1iso1 in the presynaptic compartment, which was confirmed by microelectrode array analysis. Together, our results suggest that BIN1 expression in the presynaptic terminal, but not the postsynaptic terminal leads to an isoform-specific, deleterious effect on synaptic integrity. BIN1 synaptotoxicity could contribute to the synapse loss observed early in AD. This supports the idea that genetic determinants could make synapses prone to failure in AD.

neuroscience↗

bioRxiv2021

The Alzheimer's disease genetic risk factor BIN1 induces isoform-dependent neurotoxicity through early endosome defects

The Bridging Integrator 1 (BIN1) gene is a major susceptibility gene for Alzheimers disease (AD). Deciphering its pathophysiological role is challenging due to its numerous isoforms. Here we observed in Drosophila that human BIN1 isoform1 (BIN1iso1) overexpression, contrary to BIN1iso8 and BIN1iso9, induced an accumulation of endosomal vesicles and neurodegeneration. Systematic search for endosome regulators able to prevent BIN1iso1-induced neurodegeneration indicated that a defect at the early endosome level is responsible for the neurodegeneration. In human induced neurons (hiNs) and cerebral organoids, BIN1 knock-out resulted in the narrowing of early endosomes. This phenotype was rescued by BIN1iso1 but not BIN1iso9 expression. Finally, BIN1iso1 overexpression also led to an increase in the size of early endosomes and neurodegeneration in hiNs. Altogether, our data demonstrate that the AD susceptibility gene BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation, which is an early pathophysiological hallmark of AD pathology.

neuroscience↗

bioRxiv2019

Pyk2 Overexpression in Postsynaptic Neurons Blocks Aβ1-42-induced Synaptotoxicity in a Microfluidic Co-Culture Model

Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimers disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimers disease, deciphering the impact of Alzheimers risk genes on synapse formation and maintenance is of great interest. In this paper, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid-beta (A{beta}) peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein (APP). Co-culture with cells overexpressing mutated APP exposed the synapses of primary hippocampal neurons to A{beta}1-42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of A{beta} suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta (Pyk2) -an Alzheimers disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimers disease brains at gene expression and protein levels-selectively in postsynaptic neurons is protective against A{beta}1-42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically-relevant model of Alzheimers disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.

neuroscience↗

bioRxiv2018

Expression of fatty acid transport protein in retinal pigment cells promotes lipid droplet expansion and photoreceptor homeostasis

Increasing evidence suggests that dysregulation of lipid metabolism is associated with neurodegeneration in retinal diseases such as age-related macular degeneration and in brain disorders such as Alzheimers and Parkinsons diseases. Lipid storage organelles (lipid droplets, LDs), accumulate in many cell types in response to stress, and it is now clear that LDs function not only as lipid stores but also as dynamic regulators of the stress response. However, whether these LD functions are always protective or can also be deleterious to the cell is unknown. Here, we investigated the consequences of LD accumulation on retinal cell homeostasis in transgenic flies and mice overexpressing fatty acid transport protein (FATP) in retinal pigment cells (RPCs). In wild-type Drosophila, overexpression of dFatp specifically in RPCs resulted in an expansion of LD size in both RPCs and in neighboring photoreceptors but was non-toxic. Similarly, in mice, LD accumulation induced by RPC-specific expression of human FATP1 was non-toxic and promoted mitochondrial energy metabolism in both RPCs and photoreceptor cells. In contrast, RPC-specific dFatp knockdown reduced neurodegeneration in Aats-metFB Drosophila mutants, which carry a defective respiratory chain, indicating that abnormal LD accumulation can be toxic under pathological conditions. Collectively, these findings indicate that FATP-mediated LD formation in RPCs induces a non-autonomous increase of LDs in photoreceptors that promotes homeostasis under physiological conditions but can be deleterious under pathological conditions.\n\nAuthor SummaryLipids are major cell constituents and are present in the membranes, as free lipids in the cytoplasm, or stored in vesicles called lipid droplets (LDs). Under conditions of stress, lipids stored in LDs can be released to serve as substrates for energy metabolism by mitochondria. However, lipid storage is deregulated in many degenerative disorders such as age-related macular degeneration and Alzheimers disease. Thus, it is unclear whether accumulation of LDs is protective or can also be toxic. To address this question, we examined the consequences of enforced LD accumulation on the health of retinal cells in flies and mice. Like humans, fly and mouse retinas contain retinal pigment cells (RPC) that support the functions of neighboring photoreceptor cells. We found that overexpression of the fatty acid transport protein (FATP) in RPCs induced accumulation of LDs in both transgenic flies and mice. Moreover, LD accumulation in RPCs had a beneficial effect on juxtaposed photoreceptors under normal physiological conditions, but was toxic under pathological stress conditions. We propose that lipid storage is a mechanism of cellular communication that is essential to maintain photoreceptor health.

cell biology↗